Reclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention

Alfonso Catalano, Laura Graciotti, Luciana Rinaldi, Giorgia Raffaelli, Sabrina Rodilossi, Piergiacomo Betta, Walter Gianni, Salvatore Amoroso, Antonio Procopio

Research output: Contribution to journalArticlepeer-review

Abstract

Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 × 10-5 M; p ≤ 0.05) and it elicited remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM. Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10-6 M-10-2 M), indometacin (10-6 M-10-2 M) and the COX-2 inhibitor NS-398 (10 -6 M-10-4 M). Efficacy of these different compounds was not related to the amount of COX-2 protein levels present on MM cells. Celecoxib, in a dose- and time-dependent manner, induced MM cell apoptosis, which involved decreased Akt phosphorylation, loss of Bcl-2 and Survivin protein expression and caspase-3 activation. Furthermore, vascular endothelial growth factor (VEGF), an MM autocrine growth factor and Akt inducer, rescued celecoxib-induced apoptosis and Akt dephosphorylation. When the VEGF receptor (KDR/Flk-1) inhibitor, SU-14198, was used in combination with celecoxib, IC 50 of celecoxib in vitro was reduced up to 65%. These data demonstrate that celecoxib may have antitumor properties in MM and provide a rationale for the therapeutic use of celecoxib in combination with a selective VEGF inhibitor.

Original languageEnglish
Pages (from-to)322-328
Number of pages7
JournalInternational Journal of Cancer
Volume109
Issue number3
DOIs
Publication statusPublished - Apr 10 2004

Keywords

  • Celecoxib
  • Chemoprevention
  • Mesothelioma
  • NSAIDs

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Reclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention'. Together they form a unique fingerprint.

Cite this